Extended studies on the pathophysiology of dengue haemorrhagic fever; studies on haemostasis, immunology, virology and genetic markers aimed at developing intervention strategies
06 / 2000 - 06 / 2004
- Outline: Dengue is caused by a flavivirus for which the vector is a mosquito (Aedes aegypti). In various areas of the world (South America, South East Asia) morbidity and mortality due to dengue is on the rise. The incidence of dengue in the general population in Indonesia is estimated to be 10 per 100000; during outbreaks the incidence is 27 per 100000. Among children, who are most sensitive to develop severe dengue haemorrhagic fever (DHF), these rates will be even higher. Since 1997 the infection has spread to all provinces of Indonesia and the infection has become endemic in large parts of South East Asia, including Indonesia. Clinically, three different forms with increasing severity can be distinguished: dengue fever(uncomplicated dengue: DF), dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS). The overall case fatality rate is estimated to be 1.8%, a figure that tends to double during outbreaks. The mortality rate of DSS in children was 12% in the University Hospital in Jakarta. In Semarang the mortality rate was 26% among children with DHF/DSS admitted to the intensive care unit. This figure may rise to 75% in less well equipped hospitals. In the present project we want to perform a prospective cohort study on a group of young children living in an endemic dengue area in Indonesia. The aim of this study is to elucidate the pathogenesis of complications in DHF and to develop intervention strategies, aimed at reducing morbidity and mortality of DHF in Indonesia. - Work plan: The previous study, 'Pathophysiology of dengue fever(DF); cytokines as the pivotal mediators in dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS)' granted by the KNAW (1995-1999), focussed on activation of coagulation and fibrinolysis and the relation with cytokine activation. This study provided a better insight into the origin of bleeding symptoms, although the exact sequence of events as well as the relation with activation of the cytokine network has not been elucidated. This is largely due to the fact that these studies included mainly patients with advanced disease. In the present project we want to perform a prospective cohort study. A group of young children (age 3 years; n=400) living in an endemic dengue area (Semarang / Yogyakarta, Indonesia) will be followed for 3 years. Thus we will be able to identify children with early symptoms of infection. This study enables us to get information about the pre-infection host immune status, as well as about the genetic and acquired determinants of the individual's risk of progression to DHF/DSS. The cohort study will be supplemented by an in depth survey of clinical aspects and laboratory studies in 50 children with severe DHF. Based on the results of the previous dengue research program we will focus the study on the following aspects of pathogenesis: 1. The effector mechanisms. What is the sequence of events for cytokine responses, coagulation and fibrinolysis in early infection? What is the nature of the damage to endothelial cells and what are the consequences for the derangement of coagulation? Is the tissue factor pathway a potential target for therapy? Can we recognise prognostic markers? Do changes in the serum lipid profile play a prognostic role and may this be a way for therapeutical intervention? 2. The viruses. There are four serotypes of the virus. What is the role of the different virus types? What is the role of primary versus secondary infection? 3. The immune responses. What is the B and T lymphocyte response during primary and secondary infections? Is the concept of enhancing antibodies valid? What is the meaning of the presence of a specific subgroup of lymphocytes (blue lymphocytes) in DHF? 4. The genetic background. Is susceptibility of DHF and DSS genetically determined? What is the role of genetic polymorphism of cytokines and coagulation proteins in the development of DHF?